Various forms of drug delivery systems, such as patches, capsules, and needles, are known in the art to administer drugs to a subject. Various methods of extracting blood samples, for example, making a small cut with a blade, are also available. Among the current drug delivery systems and methods of extracting blood samples, a hypodermic needle is commonly used, and is known as one of the most effective devices.
However, using a conventional hypodermic needle has several disadvantages. For example, penetration of skin using a conventional hypodermic needle may cause pain to a subject. Also, mishandling of a conventional hypodermic needle may result in infections caused by human immunodeficiency virus (HIV), hepatitis B and C viruses, etc.[1-6] Hence, many researchers have been developing hypodermic needles in small scale referred to as “microneedles,” to administer drugs or extract blood.
Employing diffusion effects, a microneedle can deliver a drug through the skin without deep penetration. Skin thickness varies depending on its location. Normally, human skin comprises three layers: stratum corneum, viable epidermis, and dermis. A microneedle can penetrate the first two layers of the human skin, which is about 150 μm, to deliver a drug effectively. For collecting blood samples from a human, the length of a microneedle should be in the range of about 500 μm.
Usually, three different materials are used for creating a hollow microneedle: silicon-based material including glass, metal, and photosensitive polymers. McAllister et al. developed a hollow microneedle based on silicon dioxide (SiO2), in out of plane and lateral fashion, using a heavy chemical etching process.[7-8] Stoeber et al. also applied a similar fabrication process to create a hollow microneedle.[9] Both McAllister et al. and Stoeber et al. used bulk micromachining technology to create the outer microneedle geometry, and used deep reactive ion etching (DRIE) or reactive ion etching (RIE) to create the hollow geometry. First, the process begins with the hollow holes created by the RIE technique followed by growing silicon dioxide thermally which will later become a needle structure. Machined Pyrex® is then anodically bonded to a silicon wafer to create a space for reservoir. At last, the silicon wafer is etched back with tetramethylammonium hydroxide to define the height of the needle. For lateral microneedles, it is fabricated by using a surface micromachining technique. A patterned silicon dioxide layer defines microchannels, and a nitride layer is deposited to create the top and side walls. Multiple ethylendiamminepyrocatechol (EDP) etches are carried out to complete the process.
Brazzle et al. created a metallic microneedle in a lateral fashion using surface micromachining technique.[10-11] The sequence of photolithography is carried out for patterning silicon nitride (Si3N4) on a heavily doped silicon substrate and etched in potassium hydroxide (KOH) to build a platform for the microneedle. Palladium is then electroplated on the patterned area to define the bottom wall followed by spinning a layer of photoresist. A 20 μm thick photoresist is patterned and developed to form the shape of the inside of the needle. Further electroplating is performed to build the side walls and top wall for encapsulating the photoresist. Finally, the photoresist is etched to leave a hollow metallic microneedle. McAllister et al. also manufactured a metallic microneedle array, which has square cross-section channel, using similar procedures. The base layer is electroplated followed by depositing and patterning a sacrificial thick photoresist. A seed layer is then sputtered onto the photoresist. Next, the side and top walls are electroplated. Finally, the photoresist is removed and the needle structure is lifted from the substrate.
A more realistic, out of plane, microneedle array has been developed by Kim et al. using a tapered negative photoresist (SU-8).[12] The tapered SU-8 post, which has angles between 3.1 to 5 degrees, is created using backside exposure on top of the SU-8 block which functions as a base. The seed layers are deposited, and electroplating is carried out to obtain 200 μm and 400 μm in length and thickness of 10 μm and 20 μm, respectively.
Moon et al. presented a different approach of microneedle fabrication using a deep X-ray to create an inclined polymeric microneedle.[13-14] The fabrication process begins with exposing polymethylemetacrylate (PMMA), a positive photoresist, under X-ray vertically followed by successive exposure in a pre-defined angle without moving the substrate. These two steps define a sharp needle tip at the region of interception of the exposures. A sharp tip angle below 40 degree is achieved with the needle length of between 600 μm to 1000 μm.
Kuo et al. reported fabrication of polymeric microneedles using SU-8.[15] A trapezoidal trench is created by potassium hydroxide (KOH) etch on 100 silicon wafer. The angle of the trench (about 35.3 degrees: measured from the vertical to the etched surface) is used to determine the angle of the beveled tip of a microneedle. After KOH etching is used to obtain the trapezoidal grooves, SU-8 is then applied and patterned using lithographic technique to create an array of hollow needle structures. Partial SU-8 development is carried out to expose the ends of the microneedle structure. These partially exposed needle structures are covered with another layer of SU-8 to form the base. The second SU-8 layer is further patterned and developed. The length of the microneedle is about 600 μm. A negative mold is also replicated with polydimethylesiloxane (PDMS). The report shows that these needles can successfully penetrate skin.
However, silicon-based microneedle structures tend to be brittle. Stiffness and toughness of metallic microneedles are still in question due to their thin walls. Flat needle tips of these metallic microneedles are not suitable for skin penetration. For microneedles made of photosensitive polymer, the stiffness of the needle structures and the strength between the needle structures and the bases are uncertain, even though the needles are capable of skin penetration.
Sparks et al. developed a microneedle array with sharp beveled tips using combinations of LIGA and soft lithography technique.[24] Two dimensional sawtooth profile was patterned on polymethylmethacrylate (PMMA) to create the beveled tip microneedle using Deep x-ray lithography (DXRL). The angle of the sawtooth design becomes the beveled angle of the final microneedle tip. The four different angles were tested from 25 to 40 degrees. The sawtooth structure is then cut in pieces, stacked on top of each other piece, turned, and the side wall was glued on a conductive substrate to form a 8×10 mm area for microneedle array. The second radiation performed on a glass slab to create a mask patterned of equilateral triangles with a hole pattern for defining the microneedle and the hollow features directly on the sawtooth structure. After exposure and partial development of the PMMA substrate, electroplating was carried out to form the metal layer around the needle structures. The thickness of the metal layer provides space for creating a base of the microneedle array. A successive development of the microneedle opens the bottom of the hollow features. Next, polyvinyl alcohol (PVA) is cast onto the microneedle array and used as a sacrificial template to replicate the microneedle array consisted of PMMA (material for actual microneedle structure) and a metal (for a base). Finally, PMMA is cast on the replicated PVA mold. Dissolving the PVA mold in water reveals the final product of plastic microneedle array. Advantage of the technique described above is that use of molding process opens the possibility of mass production for the beveled plastic microneedle array. The difficulty in assembly of sawtooth structure from the 2½ D in order to create 3D inclined structure, and in alignment of second radiation to create hollow features on the needle structure as well as use of expensive DXRL technique become disadvantages.
Perennes et al. created microneedle arrays and blades in plane by means of etching the patterned single crystal silicon.[25] First, the patterned single crystal silicon is etched to form the microchannels which will become the hollow structure in the needle. Second, fusion bonding of silicon to silicon is performed to seal the etched microchannels. Next, the plasma etching is carried out around the embedded microchannels according to the 2D beveled needle layout. At last, anisotropic etching creates the microneedle with the vertical side wall as well as it opens the microchannel on the side of the beveled surface along the vertical wall. In addition, the fabrication of microblade uses same manufacturing steps excluding creating microchannels and fusion bonding process. This technique can produce controllable 2½ D in plane microneedle arrays and microblades. However, the material used in the experiment is brittle and the cutter length of the blade is too short.
Although many microneedle fabrication processes have been developed, and there is a steady growth of using microneedles, the majority of the biomedical industry is still reluctant to adopt various microneedle fabrication techniques for needle production. A good needle structure should meet at least the following criteria: (1) adequate stiffness to prevent premature buckling failure, (2) adequate sharpness to penetrate a rubber-like skin, (3) adequate toughness to avoid particle breakage which may clog the vein, (4) sufficiency in length for use as a drug delivery or a body fluid extracting device, and (5) adequate biocompatibility.